Because of their involvement in every aspect of neuronal physiology, K+ channels of different families are regarded as potential drug targets for the treatment of various neurological disorders. K+ channel modulators may be effective in treatment of epilepsy, stroke, schizophrenia, depression and neurodegenerative disorders. Finding and characterizing new K+ channel modulators is therefore an obvious priority in neuropharmacology. However, discovery of new K+ channel modulators is limited by the low throughput capacity of existing electrophysiology-based drug screens. To overcome this limitation we are proposing a novel high throughput screening strategy based on functional expression of mammalian K+ channel Kir2.1 in yeast. Compounds that inhibit or enhance growth of yeast expressing Kir2.1 channel are selected as potential K+ channel modulators and examined in mammalian cells by patch-clamp technique. Yeast-based primary assay allows screening of chemical libraries with virtually unlimited number of compounds. The specific aims of the proposal are: 1) to perform a large scale screen of over 100,000 compounds in 4 structurally distinct chemical libraries in yeast expressing Kir2.1 channel, 2) to identify K+ channel modulators by examining action of compounds discovered in Aim 1 on Kir2.1 currents in mammalian cells, 3) to examine action of new modulators on a variety of K+ channels associated with neurological disorders and identify the most potent and specific K+ channel modulators. The study will prove the feasibility and evaluate the efficacy of the yeast-based screen. It will also provide leads for future search for highly specific and potent K+ channel modulators for use as neuropharmacological agents.